Attenuation of morphine tolerance, withdrawal-induced hyperalgesia, and associated spinal inflammatory immune responses by propentofylline in rats
Abstract
The activation of glial cells and enhanced proinflammatory cytokine expression at the spinal cord has been implicated in the development of morphine tolerance, and morphine withdrawal-induced hyperalgesia. The present study investigated the effect of propentofylline, a glial modulator, on the expression of analgesic tolerance and withdrawal-induced hyperalgesia in chronic morphine-treated rats. Chronic morphine administration through repeated subcutaneous injection induced glial activation and enhanced proinflammatory cytokine levels at the lumbar spinal cord. Moreover, glial activation and enhanced proinflammatory cytokine levels exhibited a temporal correlation with the expression of morphine tolerance and hyperalgesia. Consistently, propentofylline attenuated the development of hyperalgesia and the expression of spinal analgesic tolerance to morphine. The administration of propentofylline during the induction of morphine tolerance also attenuated glial activation and proinflammatory cytokines at the L5 lumbar spinal cord. These results further support the hypothesis that spinal glia and proinflammatory cytokines contribute to the mechanisms of morphine tolerance and associated abnormal pain sensitivity.
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Inhibition of pro-inflammatory cytokines reversed the development of morphine tolerance and withdrawal-induced hyperalgesia.
“Inhibition of pro-inflammatory cytokines reversed the development of morphine tolerance and withdrawal-induced hyperalgesia.”
From Stress- and Glucocorticoid-Induced Priming of Neuroinflammatory Responses: Potential Mechanisms of Stress-Induced Vulnerability to Drugs of Abuse (2011) · cites this paper as Raghavendra et al., 2004
Chronic morphine activated glia and up-regulated the expression of pro-inflammatory cytokines (IL-1β, IL-6, and TNFα).
“Similarly, chronic morphine activated glia and up-regulated the expression of pro-inflammatory cytokines (i.e. IL-1β, IL-6, and TNFα) (Raghavendra et al., 2004).”
From Stress- and Glucocorticoid-Induced Priming of Neuroinflammatory Responses: Potential Mechanisms of Stress-Induced Vulnerability to Drugs of Abuse (2011) · cites this paper as Raghavendra et al., 2004
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- Authors
- Raghavendra, V., Tanga, F. Y., & DeLeo, J. A.
- Affiliations
- Dartmouth–Hitchcock Medical Center (US)
- Venue
- Neuropsychopharmacology
- Published
- 2003-10-08
- Volume
- 29
- Issue
- 2
- Pages
- 327-334
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- OpenAlex
- W2062728888
- Cited by
- 263
- References
- 49
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 8 · 2023: 9 · 2022: 14 · 2021: 10 · 2020: 11 · 2019: 8 · 2018: 12 · 2017: 13 · 2016: 9 · 2015: 13 · 2014: 15 · 2013: 15 · 2012: 21
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bristol-Myers Squibb
- Dartmouth College
- National Institute on Drug Abuse (DA 11276, R01DA011276)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- morphine tolerance, morphine withdrawal, propentofylline, inflammatory cytokines, chronic morphine administration, analgesic tolerance, neuropathic pain
- MeSH terms
- Analysis of Variance, Animals, Behavior, Animal, Drug Interactions, Drug Tolerance, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Hyperalgesia, Inflammation, Male, Morphine, Morphine Dependence, Pain Measurement, Reaction Time, RNA, Messenger, Spinal Cord, Substance Withdrawal Syndrome, Xanthines, Macrophage-1 Antigen, Cytokines, Rats, Sprague-Dawley, Neuroprotective Agents, Reverse Transcriptase Polymerase Chain Reaction, Rats
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